Terms of reference

Invited experts who agreed to be part of the workshop were from the E.U., U.S. and Japan and represented academia, regulatory authorities and industry. Wider participation from regulatory authorities would have been welcome for addressing this controversial “low dose” issue.

The purpose of this group was to discuss, review and if appropriate amend the following hypotheses and to propose and agree a course of action whereby these or amended hypotheses could be investigated. It should be recognised that the starting draft hypotheses were devised in order to stimulate workshop discussion and do not represent the views of the organising committee or of workshop participants.

1. Endocrine active chemicals do not have a threshold below which adverse effects are not seen and should be regarded and tested in a different way to chemicals acting through other modes of action.

2. At low dose / exposure levels, endocrine active chemicals exhibit non-monotonic dose responses.

3. When mixed at low doses, endocrine active chemicals produce effects greater than those which may be predicted from simple dose addition.

Before considering the hypotheses in detail the group thought it important to review and agree on some key definitions of terms commonly used in this area and as they apply to the hypotheses.

‘Adverse’. The definition as described by IPCS/WHO supplemented by the further definition contained in the IPCS Mode of Action (MoA) document were agreed and it was recognised that this definition would cover events that may be initiated by exposure during sensitive windows.

‘Non-Monotonic dose response’. This can be defined as a change in direction of the relationship between response and changing dose; it should not be confused with a plateau of response.

‘Low Dose’. For the purposes of this workshop low dose was agreed to mean dose levels within the range of known or predicted human exposure levels. However some participants felt that consideration should also be given to dose levels associated with small effects independent of their numerical values.

‘Threshold’. An exposure level below which there are no adverse health effects and no such effects can be predicted based on knowledge of key events and MoA.